Highlights from Recent Cancer Literature
Journal: Cancer Research (2015)

Faller and colleagues demonstrate that loss of adenomatous polyposis coli (APC) in colorectal cancer promotes mTOR complex 1 (mTORC1)–mediated protein synthesis to drive proliferation in vivo. Surprisingly, mTORC1 activation following Apc loss did not affect the initiation of protein synthesis, but rather accelerated translation elongation in murine enterocytes. This increased efficiency in translation was attributed to the activity of ribosomal S6 kinase (S6K, RPS6KB1), an mTORC1 downstream effector, which inhibits eukaryotic elongation factor 2 (EEF2) kinase and thus promotes EEF2-mediated translation. Importantly, inhibition of MTOR using rapamycin blocked protein synthesis and the proliferative phenotype following Apc deletion without affecting ApcWT enterocytes. Moreover, rapamycin treatment of mice exhibiting targeted intestinal Apc deletion (intestinal tumor model) not only prevented tumor initiation but also promoted regression of established adenomas, resulting in significantly improved survival.Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 2014 Nov 5 [Epub ahead of print].Crystal and colleagues integrated the genetics of ALK and EGFR-driven lung cancers with pharmacologic analyses of cells derived from matched therapy-resistant patient tumors. Resistant cell lines from clinical specimens using irradiated feeder cells developed at an exceptional rate. An unbiased screen was performed combining the original tyrosine kinase inhibitor (against the driver oncogene) with a custom panel of 76 targeted agents validated in cells with known mechanisms of resistance and applied to 55 patient-derived models. In vivo and functional studies revealed that SRC inhibition resensitized ALK-driven cancers to ALK inhibition. Remarkably, mutations in SRC family kinases and regulators were not found, highlighting the need for complementary genetic analyses. These studies identify clinically relevant mechanisms of resistance and therapeutic strategies for individual patients.Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 2014;346:1480–6.Tumor cell invasion requires the coordination of adhesion, locomotion, matrix degradation, and whole cell body translocation. How these events coordinate to provide matrix dissolution, while enabling adhesion and movement, is not clear. Now Moshfegh and colleagues reveal that the GEF (guanine nucleotide exchange factor) Trio and activation of RAC1 and PAK1 signaling orchestrate invadopodia formation and turnover. Imaging of a FRET-based biosensor at single-cell resolution revealed that RAC1 activity was excluded from the invadopodia, resulting in stabilization. Forced activation using a photo-activatable form of RAC1 revealed rapid dissolution of invadopodia via cortactin phosphorylation. These studies clarify how tumor cells dynamically coordinate invadopodia formation via small GTPases, enabling efficient invasion.Moshfegh Y, Bravo-Cordero JJ, Miskolci V, Condeelis J, Hodgson L. A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly. Nat Cell Biol 2014;16:574–86.Stanisavljevic and colleagues show that cancer-associated fibroblasts (CAF) increase the rigidity of the extracellular matrix (ECM) and promote anisotropic fiber orientation to enhance tumor cell migration and invasion. The authors further demonstrate that SNAIL1/RHOA/α-SMA signaling mediates this mechanical signaling. Loss- and gain-of-function studies in cells and wound healing studies in mice were conducted to clarify roles for SNAIL1 (Snail1) in regulating ECM organization. Human breast cancer specimens with CAF-expressing SNAIL1 showed lymph node involvement, desmoplastic areas with anisotropic fibers, and poor outcomes. Thus, the authors identify a novel function of SNAIL1 in CAF that regulates ECM reorganization and cancer invasion.Stanisavljevic J, Loubat-Casanovas J, Herrera M, Luque T, Pena R, Lluch A, et al. Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis. Cancer Res; Published OnlineFirst December 8, 2014; doi:10.1158/0008-5472.CAN-14-1903.Hypothesizing that secreted factors play roles in glioma stem cell (GSC) survival, Man and colleagues investigated the Class 3 semaphorin SEMA3C. SEMA3C was overexpressed in human glioblastoma and colocalized with GSC markers CD133, OLIG2, and SOX2 in tumors and GSCs. The semaphorin coreceptors PlexinA2 (PLXNA2) and PlexinD1 (PLXND1) were also expressed in GSCs. Knockdown studies demonstrated an essential role for SEMA3C, PlexinA2, and PlexinD1 in GSC viability and tumorsphere formation. Consistent with an autocrine/paracrine role, both coculture with wild-type GSCs and soluble SEMA3C could rescue SEMA3C knockdown. The authors identified SEMA3C- and PlexinA2/PlexinD1-mediated defects in RAC1 activation. Constitutively activated RAC1 rescued the shSEMA3C-mediated defects in GSC proliferation, migration, and tumorsphere formation. Nonstem tumor cells express different semaphorins, and SEMA3C knockdown in these cells had no effect on survival. Thus, inhibition of SEMA3C may uniquely target GSCs and serve as a therapeutic target.Man J, Shoemake J, Zhou W, Fang X, Wu Q, Rizzo A, et al. Sema3C promotes the survival and tumorigenicity of glioma stem cells through Rac1 activation. Cell Rep 2014;9:1812–26.Using a mathematical model combining over 200 scientific publications, Chanrion and colleagues found that dissemination of colon cancer was intimately linked to epithelial-to-mesenchymal transition (EMT). The authors pinpointed two key events necessary for cancer cells to transition toward metastasis: simultaneous activation of the NOTCH1 receptor and loss of p53. The researchers developed a mouse model combining these two genomic changes. In line with the predictions emerging from the clinical data, these animals developed numerous metastases in multiple organs. Importantly, disseminated cells showed specific characteristics of cells having undergone EMT. This study developed a model that recapitulates cellular features observed in invasive human colorectal tumors, and is appealing for innovative drug discovery.Chanrion M, Kuperstein I, Barrière C, El Marjou F, Cohen D, Vignjevic D, et al. Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. Nat Commun 2014 Oct 8;5:5005.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.